The fluctuating response to levodopa in Parkinson's disease ("on- off" phenomenon) is a common, disabling problem that occurs during chronic levodopa therapy and is resistant to current modes of therapeutic manipulation. Our goal is to understand why this fluctuating response develops and what determines the minute-to- minute motor function. This understanding is to foundation on which to design improved therapeutic strategies to treat the fluctuating response or prevent its development. This proposal will 1) explore the importance of plasma large neutral amino acid (LNAA) concentrations on response to levodopa in parkinsonian patients by determining how much plasma amino acids vary during the day, whether the ratio of plasma levodopa to LNAA concentrations is a better predictor of response and whether fasting LNAA concentrations correlate with minimum therapeutically effective plasma levodopa concentrations; 2) to investigate the possibility of a biphasic response to levodopa (both inhibitory and excitatory actions) by comparing responses to placebo, subthreshold, threshold, and suprathreshold infusion rates and the possibility of tolerance by determining the effect of constant intraduodenal infusions for 5 days on sensitivity to apomorphine and; 3) examine central pharmacokinetics of levodopa in stable and fluctuating patients by establishing dose response curves for levodopa and apomorphine to judge whether sensitivity to drug kinetics in the effector compartment is different between stable and fluctuating patients and; 4) as another index of central pharmacokinetics; study the relationship between plasma and CSF levodopa in dogs and neurosurgical patients and subsequently CSF levodopa and response in parkinsonian patients. These experiments will help define factors which modify the response to levodopa as well as the phenomenon which underlie the development of the fluctuating response.